A team led by Johns Hopkins scientists has
found the first clear evidence that the process behind the human immune
system's remarkable ability to recognize and respond to a million
different proteins might have originated from a family of genes whose
only apparent function is to jump around in genetic material.
"Jumping genes"
essentially cut themselves out of the genetic material, and scientists
have suspected that this ability might have been borrowed by cells
needing to build many different proteins from a specific, single set of
instructions -- the key to recognizing a million immune-stimulating
proteins. But until now, no jumping gene was known to behave just right.

Writing
in the Dec. 23 issue of Nature, the researchers show that a jumping
gene called Hermes, still active in the common house fly, creates
changes in DNA very much like those created by the process behind
antigen recognition.
"Hermes behaves more like the process used by the immune system to
recognize a million different proteins, called antigens, than any
previously studied jumping gene," says Nancy Craig, Ph.D., professor of
molecular biology and genetics in Johns Hopkins' Institute for Basic
Biomedical Sciences and a Howard Hughes Medical Institute investigator.
"It provides the first real evidence that the genetic processes behind
antigen diversity might have evolved from the activity of a jumping
gene, likely a close relative of Hermes."
Recognition of so many antigens allows the immune system to fight
infection and distinguish friend from foe. The "big picture" behind
this ability is that cells build proteins called antibodies that bind
to particular antigens, but the early steps of that process have been
difficult to study. Hermes should help reveal some secrets of this
process, the researchers say.
"The immune system takes an approach to protein building similar to
that of diners creating a meal at a cafeteria, but how the immun
e
system's 'a la carte' process happens is still murky," says Craig.
But the a la carte approach provides great diversity from a limited
number of choices, whether in the immune system or in a cafeteria. For
example, at a cafeteria, one diner could have a meal of mashed
potatoes, broccoli and a pork chop, and another French fries, salad and
a hamburger, and so on through all the possible combinations of
offerings.
While the choices aren't as tasty, immune cells select sections of
certain genetic instructions in order to make instructions for a
protein that will recognize a particular antigen. Machinery snips out
unwanted genetic sections and reconnects the leftover ones, creating a
unique gene (the cellular equivalent of the diner's meal). Snipping out
different sections will lead to a different gene, carrying instructions
for a different protein that will recognize a different antigen, and on
and on.
This a la carte process, known as V(D)J recombination, is similar to
the excision of jumping genes, but none had matched one of its
characteristic oddities: As the unwanted DNA is being removed, the
remaining DNA forms a tiny loop.
Unexpectedly, when Hermes is being cut out of the DNA, the leftover DNA
also forms a hairpin loop, temporarily doubling back on itself,
postdoctoral fellows Liqin Zhou, Ph.D., and Rupak Mitra, Ph.D.,
discovered in experiments in test tubes and with E. coli bacteria.
Although this loop distances Hermes from its well-studied cousins, the
Hermes protein still has an important family trait, the researchers
report. Colleagues at the National Institutes of Health found that a
few key building blocks in the protein's DNA-snipping crevice are
identical to those in other jumping genes' proteins, even though the
overall sequence is quite different.
"Because of its similarities both to V(D)J recombination and to other
families of jumping genes, Hermes is the first real link between the
two processes," says Craig. "It also is likely to be a good model t
o
figure out what's happening early on in V(D)J recombination."
Understanding how Hermes and other jumping genes work also holds clues
to fighting bacterial infections, improving gene therapies and tackling
disease-carrying insects, Craig notes. Bacterial jumping genes can
protect bacteria from certain antibiotics. Scientists also are studying
jumping genes as vectors to carry gene therapies and as potential
modifiers to disrupt the growth-controlling genes of organisms such as
mosquitoes and medflies.
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